David W. Hudgel

Inhibition of theophylline clearance by troleandomycin

The effect of troleandomycin, a macrolide antibiotic, on theophylline elimination was examined in eight patients with chronic asthma. Clearance from serum was reduced by 50 +/- 6% (mean +/- SD) during administration of 250 mg troleandomycin four times daily. Reduction of clearance persisted to a lesser degree in one of these patients examined while receiving 250 mg troleandomycin daily. An increase in serum theophylline concentration can thus result from initiating troleandomycin in asthmatic patients receiving continuous treatment with theophylline. This may be at least a partial explanation for the apparent benefit of troleandomycin in chronic asthma and also suggests that possibility of inducing theophylline toxicity, including seizures, as was observed in one of the patients in this study.

Prevalence and Polysomnographic Correlates of Insomnia Comorbid with Medical Disorders

STUDY OBJECTIVES To determine the prevalence and polysomnographic correlates of insomnia in subjects with self-reported medical disorders. DESIGN Prospective cross-sectional study. PARTICIPANTS Community-based sample of 3282 men and women aged 18 to 65 years old, with a subset who underwent polysomnography. MEASUREMENTS Self-reported measures of sleep habits and current health, and polysomnographic sleep variables. RESULTS The prevalence of insomnia was 21.4%. The adjusted odds of insomnia were 2.2 times as high in persons with any medical disorders as in those without medical disorders. Specifically, odds of insomnia were higher in people with heart disease (OR = 1.6 [95% CI: 1.2-23], P = 0.004), hypertension (1.5 [12-18], P < 0.001), diabetes (1.4 [105-20], P = 0.04), stomach ulcers (2.1 [1.6-2.7], P < 0.001), arthritis (1.8 [1.5-2.2], P < 0.001), migraine (1.8 [1.5-2.1], P < 0.001), asthma (1.6 [1.3-2.0], P = 0.04), COPD (1.9 [1.5-2.5], P < 0.001), neurological problems (2.0 [1.5-2.7], P < 0.001), and menstrual problems (1.7 [1.3-2.1], P < 0.001) than in people without these disorders. Prevalence of insomnia increased with increasing number of medical disorders. However, polysomnographic sleep was not significantly different in persons with or without medical disorders for most disorders assessed. CONCLUSION This large population-based study suggests that insomnia is highly prevalent in diverse chronic medical disorders. However, polysomnographic evidence of disturbed sleep is present in only a subset of comorbid insomnia populations.

Hypoglossal and phrenic motoneuron responses to serotonergic active agents in rats

5-Hydroxytryptamine (serotonin, 5-HT) affects upper airway and chest wall inspiratory muscle control. The purpose of this study was to investigate the relative interaction of serotonergic agents on these two muscle groups. We measured the responses of the hypoglossal and phrenic nerves to the systemic administration of serotonergic-active agents and determined the receptor types through which these agents act in anesthetized, vagotomized, paralyzed and artificially ventilated rats. The serotonin precursor, L-5-hydroxytryptophan (L-5-HTP) produced equivalent stimulation of phasic inspiratory activity of the hypoglossal and phrenic nerves. General serotonin antagonists produced significant and equivalent diminution of both motoneuron pools. Specific 5-HT1A stimulation and 5-HT1C/2 antagonism enhanced ventilatory activity. We conclude: (1) a baseline level of serotonergic input to hypoglossal and phrenic motoneuron pools was present, (2) different 5-HT receptors had different effects on ventilatory neural activity, and (3) hypoglossal and phrenic motoneuron pools responded similarly to the serotonergic agents given.

Continuous Positive Airway Pressure in Severe Obstructive Sleep Apnea Reduces Pain Sensitivity

STUDY OBJECTIVE To evaluate effects of CPAP on pain sensitivity in severe OSA patients. DESIGN Within-subject treatment study. SETTING Hospital-based sleep disorders center. PATIENTS Twelve severe OSA patients (7 men, 5 women), 50.2 ± 12.5 years, with no pain. INTERVENTIONS The morning after a diagnostic nocturnal polysomnogram (NPSG), patients underwent a training session of finger withdrawal latency (FWL) testing to a radiant heat stimulus, a validated human behavioral model of thermal nociception. Baseline FWL in seconds was obtained after the training session. CPAP pressure was titrated on a second night in the laboratory. Two nights after titration, patients returned to sleep in the laboratory on CPAP. FWL was tested in the morning after awakening, after 6-8 wks of CPAP use, and finally (within 6-8 weeks) after 2 nights of discontinuation of CPAP. Mean FWL in seconds (sec) was compared using MANOVAs with nights as the within subject variable. RESULTS Apnea-hypopnea index (AHI) decreased from 50.9 ± 14.5 to 1.4 ± 1.0 with CPAP, and sleep continuity improved. In parallel, FWL increased significantly from a mean baseline of 9.8 ± 1.3 sec to 13.7 ± 5.1 sec (P = 0.01) and with continued CPAP use (5.1 ± 2.3 h nightly) for 6-8 weeks FWL remained elevated (21.1 ± 16.2 sec). After the 2-night CPAP discontinuation, apnea/hypopneas returned and sleep was fragmented (AHI = 32.6 ± 19.8). FWL decreased to 11.6 ± 5.9 sec relative to intermediate-term CPAP use (P = 0.03). CONCLUSION CPAP treatment reduces pain sensitivity in OSA patients. Future studies will focus on patients with OSA and chronic pain and identify mediating mechanisms.

Comparative levels of excessive daytime sleepiness in common medical disorders.

INTRODUCTION Sleep restriction and sleep disorders are common causes of excessive daytime sleepiness (EDS). Medical disorders (MD) can also cause EDS, but previous studies have used non-standardized measures, selected samples, or have examined EDS in singular disorders. This study describes the relative degree of EDS associated with medical disorders to provide comparative data across a range of common medical conditions in a large unselected community-based sample. METHODS Responses of 2612 individuals (aged 18-65) were assessed after excluding those with suspected sleep disordered breathing, narcolepsy, and shift workers. Participants across a range of medical disorders were evaluated using the Epworth Sleepiness Scale (ESS) and patient reports of nocturnal sleep. RESULTS Sixty-seven percent of the sample reported a MD. The prevalence of EDS (ESS>or=10) was 31.4% in individuals with MD and increased as a function of a number of MD (0 MD=29.4%, 1 MD=28.4%, 2 MD=31.0%, 3 MD=35.3%, 4 MD=38.4%). Disorders which were independent predictors of EDS were ulcers OR=2.21 (95% CI=1.35-3.61), migraines OR=1.36 (95% CI=1.08-1.72), and depression OR=1.46 (95% CI=1.16-1.83) after controlling for other conditions, age, gender, time in bed, caffeine, smoking and alcohol use. Participants with ulcers had the highest prevalence of sleepiness, 50.0%, as well as the highest level of problems falling asleep (40.8%) and awakenings during the night (62.5%). CONCLUSIONS Individuals with ulcers, migraines, and depression have independent and clinically significant levels of EDS relative to other common MD.

Assessment of Multiple Health Risks in a Single Obstructive Sleep Apnea Population

STUDY OBJECTIVES In order to provide a comprehensive estimate of the health risks for OSA patients, we analyzed multiple outcomes and independent predictors of these outcomes in an OSA population evaluated and followed at one sleep center. METHODS Cox proportional hazard regression analyses were used in an 8-year follow-up analysis of consecutive OSA patients (N = 1025) and non-apneic snorers (apnea-hypopnea index < 5, N = 494). RESULTS In our fully adjusted model, independent variables predictive of all-cause mortality, myocardial infarction, cerebral vascular accident, and pulmonary embolus were: older age, male gender, and history of cardiovascular diseases or procedures. In examining subgroups based on age and gender, severe OSA (AHI ≥ 30) was one of the independent predictors of mortality in males and in patients < 50 years old. Severe OSA interacted with maleness, age, and hypertension to predict mortality and myocardial infarction. CPAP use ≥ 4 h/night was associated with lower mortality rates in males and those ≥ 50 years old with severe OSA. CONCLUSIONS Mortality and cardiovascular event outcomes were predicted by demographics and cardiovascular disease history more commonly than by OSA severity. OSA severity was an important predictor of mortality in male and young OSA patients. CPAP use appeared protective in older and male severe OSA patients.

Neuropsychiatric manifestations of obstructive sleep apnea: a review.

Obstructive sleep apnea (OSA) may result in neuropsychiatric complications. Psychiatrists need to be alert to the possibility that patients who present to them with cognitive and/or affective disorders, who also have sleep related complaints such as snoring and significant daytime hypersomnolence, may have OSA. Clinical suspicion needs to be reinforced by obtaining a history from the bed partner. A polysomnogram will establish the diagnosis. Once the diagnosis is made, several treatment options are available. Treatment of sleep apnea usually leads to a resolution, or at least improved control, of the complicating neuropsychiatric disorder. Physicians must be aware that sedating neuroleptic or antipsychotic agents may worsen sleep apnea and, thereby, aggravate the neuropsychiatric disturbance.

Influence of neighbourhood-level crowding on sleep-disordered breathing severity: mediation by body size

Neighbourhood‐level crowding, a measure of the percentage of households with more than one person per room, may impact the severity of sleep‐disordered breathing. This study examined the association of neighbourhood‐level crowding with apnoea–hypopnoea index in a large clinical sample of diverse adults with sleep‐disordered breathing. Sleep‐disordered breathing severity was quantified as the apnoea–hypopnoea index calculated from overnight polysomnogram; analyses were restricted to those with apnoea–hypopnoea index ≥5. Neighbourhood‐level crowding was defined using 2000 US Census tract data as percentage of households in a census tract with >1 person per room. Multivariable linear mixed models were fit to examine the associations between the percentage of neighbourhood‐level crowding and apnoea–hypopnoea index, and a causal mediation analysis was conducted to determine if body mass index acted as a mediator between neighbourhood‐level crowding and apnoea–hypopnoea index. Among 1789 patients (43% African American; 68% male; 80% obese), the mean apnoea–hypopnoea index was 29.0 ± 25.3. After adjusting for race, age, marital status and gender, neighbourhood‐level crowding was associated with apnoea–hypopnoea index; for every one‐unit increase in percentage of neighbourhood‐level crowding mean, the apnoea–hypopnoea index increased by 0.40 ± 0.20 (P = 0.04). There was a statistically significant indirect effect of neighbourhood‐level crowding through body mass index on the apnoea–hypopnoea index (P < 0.001). Neighbourhood‐level crowding is associated with severity of sleep‐disordered breathing. Body mass index partially mediated the association between neighbourhood‐level crowding and sleep‐disordered breathing. Investigating prevalent neighbourhood conditions impacting breathing in urban settings may be promising.

Critical review: CPAP and weight management of obstructive sleep apnea cardiovascular co-morbidities

The cardiovascular co-morbidities of obstructive sleep apnea (OSA) are similar to those of obesity. Cardiovascular co-morbidities often are the cause of adverse outcomes in overweight/obese OSA patients. Continuous positive airway pressure (CPAP) therapy resolves the symptoms of OSA, but may, or may not lead to improvement of a given cardiovascular co-morbidity. The impact of CPAP on cardiovascular risk variables, adverse cardiovascular events in overweight/obese OSA patients has been evaluated primarily in prospective, uncontrolled cohort studies. These studies show improvement in myocardial and endothelial function, blood pressure, left ventricular performance and stroke survival. Randomized controlled studies (RCTs) examining the effect of weight management on cardiovascular risk factors and disease outcomes show that intentional weight loss leads to improvement in cardiovascular risk, hypertension, coronary artery disease, but not in stroke. Weight loss improves mortality in relatively healthy overweight/obese populations, but possibly not in all groups with cardiometabolic diseases. Clinicians caring for overweight/obese OSA patients should consider the advantages of incorporating weight management into their treatment programs for such patients.

The carotid body in the motorneuron response to protriptyline

Protriptyline (PRT) has been shown to preferentially stimulate upper airway inspiratory motorneurons relative to phrenic activity in hyperoxic hypercapnia in the decerebrate cat via a carotid body-independent mechanism. Since previous studies indicated that carotid body stimulation results in preferential activation of upper airway respiratory muscles during both hypercapnia and hypoxemia, we hypothesized that if PRT preferentially stimulated upper airway motorneurons, the mechanism of action might involve the carotid body. We investigated the effect of PRT on carotid body function by comparing the electrical activity of the hypoglossal (HYP) with that of the phrenic (PHR) nerve in carotid sinus nerve intact (CSNI) and CSN-sectioned (CSNX) anesthetized rats, before and after PRT (0.5 mg/kg i.v.), during 100% O2, 15% O2 (N2 balance), and 4% CO2 (O2 balance) administration. The moving time average (MTA) peak inspiratory electroneurogram activities of both the HYP and PHR nerves increased an equivalent amount after PRT injection during hyperoxia, in both CSNI and CSNX rats. During hypoxia, the HYP activity increased significantly more than the PHR activity only in CSNI rats after PRT injection. During hyperoxic hypercapnia, HYP MTAs increased a similar amount in the CSNI and CSNX rats. We conclude that the HYP and PHR respiratory motorneuron pool responses to PRT depend on the blood gas status at the time of drug administration.